The present invention relates to novel UCF116 derivatives or salts thereof which have antitumor and antibacterial activities and are useful as antitumor agents. Also, the present invention relates to a pharmaceutical composition which comprises the UCF116 derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Compounds which are represented by the following structural formulae, namely UCF116-B and UCF116-D (WO 96/15114), mycotrienin II and mycotrienin I [Journal of Antibiotics, 35:1460, 1467, 1474 (1982), Tetrahedron Letters, 32:841 (1991)], T-23-VIII and T-23-IX (U.S. Pat. No. 4,587,237), ansatrienin A2 and ansatrienin A3 [Journal of Antibiotics, 36:187 (1983)], ansatrienin A4 [Journal of Natural Products, 50:108 (1987)] and hexadehydromycotrienin II [The Journal of Biological Chemistry, 270:25949 (1995) are known. It has been reported that these compounds have antibacterial activities and antitumor activities. 
Although studies have been widely made on antitumor agents efficacious on solid tumors, there are only few antitumor agents having low toxicity. The present inventors investigated antitumor agents efficacious on solid tumors and, as a result, found that UCF116 derivatives are efficacious on solid tumors while showing low toxicity, thus completing the present invention.
The present invention relates to UCF116 derivatives represented by formula (I): 
wherein
Q represents 
and
R represents
hydrogen,
C(xe2x95x90O)R1a (wherein
R1a represents
methyl,
ethyl,
propyl,
isopropyl,
2,2-dimethylpropyl,
pentyl,
alkyl having 6 to 10 carbon atoms,
1-propenyl,
isopropenyl,
2-methyl-1-propenyl,
substituted or unsubstituted alicyclic alkyl having 3 to 5 carbon atoms,
substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl,
a substituted or unsubstituted heterocyclic group,
substituted or unsubstituted aralkyloxy,
or
substituted lower alkyl),
C(xe2x95x90X)NHR1b (wherein
X represents
an oxygen or sulfur atom, and
R1b represents
substituted or unsubstituted lower alkyl,
substituted or unsubstituted alicyclic alkyl,
substituted or unsubstituted lower alkoxycarbonyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, or
a substituted or unsubstituted heterocyclic group), or
SO2R1c (wherein
R1c represents
substituted or unsubstituted lower alkyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl,
a substituted or unsubstituted heterocyclic group, or
substituted or unsubstituted lower alkenyl),
with the proviso that, when Q is 
R is not benzoyl,
salts thereof, isomers thereof, hydrates thereof, or solvates thereof.
Furthermore, the present invention relates to a pharmaceutical composition, which comprises the above-described derivative, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, and a pharmaceutically acceptable carrier.
Moreover, the present invention relates to an antitumor agent or antibacterial agent, which comprises as an active ingredient the above-described derivative, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof.
Hereinafter, the compound represented by formula (I) is referred to as Compound (I). The same shall apply to compounds of other formula numbers.
In the definition of each group in formula (I), examples of the lower alkyl include straight- or branched-chain alkyls having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, and decyl.
Examples of the alkyl having 6 to 10 carbon atoms include those having 6 to 10 carbon atoms among the above-described lower alkyls.
Examples of the alicyclic alkyl include those having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl.
Examples of the alicyclic alkyl having 3 to 5 carbon atoms include those having 3 to 5 carbon atoms among the above-described alicyclic alkyls.
A lower alkyl moiety contained in the lower alkoxycarbonyl has the same meaning as the above-described lower alkyl.
Examples of the lower alkenyl include straight- or branched-chain or cyclic alkenyls having 2 to 8 carbon atoms, such as vinyl, allyl, crotyl, 1-propenyl, prenyl, isopropenyl, 2-methyl-2-butenyl, pentenyl, hexenyl, heptenyl, octenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
The aryl is a mono- to tricyclic carbon ring composed of three- to seven-membered rings in which at least one ring is an aromatic ring. Examples include phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, indanyl, and phenanthrenyl.
Examples of the aralkyl include those having 7 to 15 carbon atoms, such as benzyl, phenetyl, benzhydryl, naphthylmethyl, and fluorenylmethyl.
An aralkyl moiety contained in the aralkyloxy has the same meaning as the above-described aralkyl.
The heterocyclic group means a mono- to tricyclic ring composed of three- to eight-membered rings having 1 to 7 carbon atoms and contains at least one of nitrogen, oxygen and sulfur atoms. Examples include heterocyclic groups, such as azepinyl, benzimidazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, furyl, imidazolidinyl, imidazolyl, imidazothiazolyl, indolinyl, indolyl, isochromanyl, isoindolyl, isoxazolyl, isoquinolyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopyrrolinyl, 2-oxopyrrolidinyl, piperidinyl, piparazinyl, pyridyl, pyrrazinyl, pyrazolinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, imidazothiazolyl and triazolyl.
A substituent on the lower alkyl, alicyclic alkyl, alicyclic alkyl having 3 to 5 carbon atoms, lower alkenyl, lower alkoxycarbonyl, aryl, aralkyl, aralkyloxy or heterocyclic group is 1 to 3 substituents which are the same or different, such as hydroxy, halogen, nitro, amino, carboxy, cyano, lower alkyl, alicyclic alkyl, lower alkenyl, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, aryl, aryloxy, aryloxy(lower alkyl), lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, aralkyl, aralkyloxy, arylamino, arylsulfonyl, and a heterocyclic group. In the definition of the substituents, the halogen means a fluorine, chlorine, bromine or iodine atom, and the lower alkyl, alicyclic alkyl, lower alkenyl, lower alkoxycarbonyl, aryl, aralkyl, aralkyloxy and heterocyclic group have the same meanings as defined above. Also, the lower alkyl moiety contained in the lower alkoxy, lower alkanoyl, lower alkylthio, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino or aryloxy(lower alkyl) has the same meaning as the above-described lower alkyl. The aryl moiety in the aryloxy, aryloxy (lower alkyl), arylamino and arylsulfonyl has the same meaning as the above-described aryl. Additionally, the substituent may be further substituted with a similar substituent. For example, the alkyl and aryl moieties of the above-described substituent may be substituted with 1 to 3 halogen atoms and the heterocyclic group may be substituted with 1 to 3 substituents such as lower alkyl and trifluoromethyl.
Compound (I) may form a salt, and examples of the salt and pharmaceutically acceptable salt of Compound (I) include an acid addition salt, a metal salt, an ammonium salt, an organic amine addition salt and an amino acid addition salt. Examples of the acid addition salt include an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, nitrate) and an organic acid addition salt (e.g., formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, methanesulfonate, p-toluenesulfonate, aspartate, glutamate). Examples of the metal salt include an alkali metal salt (e.g., lithium salt, sodium salt, potassium salt) and an alkaline earth metal salt (e.g., magnesium salt, calcium salt) an aluminum salt, and a zinc salt. Examples of the ammonium salt include ammonium and tetramethylammonium. Examples of the organic amine addition salt include an addition salt of morpholine or piperidine. Examples of the amino acid addition salt include an addition salt of glycine, phenylalanine, glutamic acid, or lysine.
Compound (I) may exist as a various isomer, such as a position isomer, a stereoisomer, an optical isomer, and a tautomer, and all possible isomers and their mixtures of every ratio are also included in the present invention.
Also, Compound (I) and pharmaceutically acceptable salts thereof may exist in the form of an adduct with water or various solvents, and such adducts are also included in the present invention.
Next, methods for the production of Compound (I) are described.
Among compounds of formula (I), Compound (I) in which Q is 
can be produced for example by the following reaction steps. 
(In the above reaction scheme and the following description, FMOC, Ala, DMAP, and DBN represent 9-fluorenylmethoxycarbonyl, alanine, N,N-dinethylaminopyridine, and 1,5-diazabicyclo[4.3.0]non-5-ene, respectively.)
Compound 2 in which R1 in formula (I) is hydrogen can be synthesized from a known compound, mycotrienol I, which can be obtained from UCF116-B or mycotrienin II in accordance with the reported methods [Tetrahedron Letters, 23:59 (1982)], Journal of Antibiotics, 35:1474 (1982)]. That is, in accordance with the reported method [Tetrahedron Letters, 32:1627 (1991)], acid anhydride of D-alanine having an amino group protected with a 9-fluorenylmethoxycarbonyl (FMOC) group is allowed to react with mycotrienol I in the presence of a base, such as dimethylaminopyridine to synthesize Compound 1 in which the alanine residue is selectively introduced into the 11-position hydroxyl group. Compound 2 can be synthesized by removing the FMOC group of the thus obtained Compound 1 in the presence of a base, such as DBN. The protecting group of D-alanine used in this step may be any protecting group usually used in peptide synthesis, so that anhydride of alanine protected with carbobenzoxy, tert-butoxycarbonyl or the like can also be used. 
(In the above reaction scheme, R1a has the same meaning as defined above, and W represents an insoluble resin.)
Among compounds of formula (I), Compound Ia in which R is represented by C(xe2x95x90O)R1a can be synthesized by allowing Compound 2 to react with various types of acid chloride (R1aCOCl) in an inert solvent, such as dichloromethane, in the presence of a basic resin, such as (piperidinomethyl)polystyrene. After completion of the reaction, a basic resin, such as (aminomethyl)polystyrene, is further added thereto to remove excess acid chloride, the resin is removed by filtration and then the solvent is evaporated to obtain Compound Ia with a high purity. In step 2 and the following step 3 or 4, the insoluble resin represented by W means an insoluble resin generally used as a solid phase carrier in the field of combinatorial chemistry, peptide solid phase synthesis and the like, and a cross-linked polystyrene resin is used preferably. The basic solid phase carrier for use in the present invention can be obtained as a commercial item or synthesized in accordance with known methods. 
(In the above reaction scheme, R1b and X have the same meanings as defined above, and W represents an insoluble resin as defined above.)
Among compounds of formula (I), Compound Ib in which R is R1bNHCO or R1bNHCS can be synthesized by allowing Compound 2 to react with various types of isocyanate (R1bNCO) or isothiocyanate (R1bNCS) in an inert solvent, such as dichloromethane, in the presence of a basic resin, such as (piperidinomethyl)polystyrene. After completion of the reaction, a basic resin, such as (aminomethyl)polystyrene, is further added thereto to remove excess isocyanate or isothiocyanate, the resin is removed by filtration and then the solvent is evaporated to obtain Compound Ib with a high purity. 
(In the above reaction scheme, R1c has the same meaning as defined above, and W represents an insoluble resin as defined above.)
Among compounds of formula (I), Compound Ic in which R is R1cSO2 can be synthesized by allowing Compound 2 to react with various types of sulfonyl chloride (R1cSO2Cl) in an inert solvent, such as dichloromethane, in the presence of a basic resin, such as (piperidinomethyl)polystyrene. After completion of the reaction, a basic resin, such as (aminomethyl)polystyrene, is further added thereto to remove excess sulfonyl chloride, the resin is removed by filtration and then the solvent is evaporated to obtain Compound Ic with a high purity.
In the above steps 2 to 4, respective compounds of interest can also be obtained using an organic base, such as pyridine, triethylamine, or DMAP, instead of a basic resin, such as (piperidinomethyl)polystyrene or (aminomethyl)polystyrene.
Compound Ie in which Q of the general formula (I) is represented by 
can be obtained from Compound Id in which Q of the general formula (I) is represented by 
in accordance, for example, with the following step. 
(In the above reaction scheme, R has the same meaning as defined above.)
Compound Ie can be synthesized by treating Compound Id with one equivalent to a large excess of a reducing agent, such as Na2S2O4, in a solvent, such as methanol.
In the above steps 1 to 4, the amount of each of the reagents or insoluble resins used is not limited to the equivalent amount described in each reaction scheme, and they can be used in an amount of 1 to 10 equivalent based on the material compound. Also, in the above steps 1 to 5, each reaction is carried out at a temperature of xe2x88x9280 to 60xc2x0 C.
In addition to the techniques described above, conversion of functional groups in the above-described production methods can also be carried out in accordance with a known method {for example, the method described in Comprehensive Organic Transformations, edited by R. C. Larock (1989)}.
Isolation and purification of respective products formed in the above-described production methods can be carried out by employing optional combinations of techniques generally used in the field of organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, and various chromatographic means.
Structures and physical properties of typical examples of Compound (I) are shown in Tables 1 to 3.
Compound (I) or a pharmaceutically acceptable salt thereof is administered orally or parenterally as it is or as various pharmaceutical compositions. The dosage form of the pharmaceutical compositions includes tablets, pills, powders, granules, capsules, suppositories, injections, and drops.
Preparation of the above dosage forms can be carried out according to conventional methods. For example, the composition may contain various excipients, lubricants, binders, disintegrators, suspending agents, isotonizing agents, emulsifiers, and absorbefacients.
Examples of the carrier used in the pharmaceutical compositions include water, distilled water for injection, physiological saline, glucose, fructose, sucrose, mannitol, lactose, starch, corn starch, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, and glycerine fatty acid ester. They are appropriately selected according to the kind of the preparation.
The dosage and administration schedule vary depending on the effect of treatment, the administration route, the period of treatment, the age, the body weight, and the like. The compound is usually administered at a dose level of 0.01 mg to 200 mg/kg once or a few times per day for an adult orally or parenterally (for example, injection, drop, intrarectal administration by suppositories, application to skin). Since the dosage depends on various factors as stated above, lower doses may be sufficient, or higher doses may be required.
The solid compositions for oral administration in the present invention include tablets, pills, capsules, powders, and granules.
The solid compositions are prepared by mixing at least one active ingredient with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate, and magnesium aluminate.
The solid compositions can contain customarily employed additives other than the inert diluent, such as lubricants (e.g., magnesium stearate), disintegrators (e.g., cellulose calcium glycolate), stabilizers (e.g., human serum albumin, lactose), and adjuvants for solubilization and dissolution (e.g., arginine, glutamic acid, aspartic acid).
The tablets or pills, if desired, can be coated with a film of a gastric or enteric substance (e.g., sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate).
The capsules include hard capsules and soft capsules.
The liquid compositions for oral administration include solutions, emulsions, suspensions, syrups, and elixirs.
The liquid compositions for oral administration can contain generally used inert diluents (e.g., purified water).
The liquid compositions can contain adjuvants, such as wetting agents, adjuvants for solubilization and dissolution, suspending agents, sweeteners, flavors, aromatics, and antiseptics in addition to the inert diluents.
Other compositions for oral administration include sprays containing at least one active ingredient, which are prepared in a conventional manner. Sprays can contain stabilizers (e.g., sodium sulfite) and buffers for making the composition isotonic (e.g., sodium chloride, sodium citrate, citric acid) in addition to the inert diluents.
The injectable preparations for parenteral administration include sterile aqueous or nonaqueous solutions, suspension or emulsions.
The injectable preparations are prepared by mixing at least one active ingredient with at least one inert aqueous diluent (e.g., distilled water for injections, physiological saline) or inert nonaqueous diluent (e.g., propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol such as ethanol, Polysorbate 80 (registered trade name)). They can further contain antiseptics, wetting agents, emulsifiers, dispersants, stabilizers (e.g., human serum albumin, lactose), and adjuvants for solubilization and dissolution.
The resulting liquid compositions are usually sterilized by filtration, incorporation of bactericides or irradiation. The sterilized composition may be solidified by, for example, freeze-drying, to obtain a solid composition, which is dissolved in aseptic water or aseptic diluent for injection on use.